The pathogenesis of Alzheimer?s disease (AD) remains unclear, though there is growing support for a synergistic relationship between vascular dysfunction and accumulation of amyloid-? and neurofibrillary tangles. Cerebrovascular disease (CVD) risk factors are prevalent in the VA population, have been linked to cognitive decline and higher risk for dementia, and may represent potential targets for remediating age-related cognitive decline. [CVD risk factors are associated with peripheral vascular (e.g., increased pulse wave velocity [PWV] indicating arterial stiffness) and cerebrovascular changes (e.g., reduced cerebral blood flow [CBF]; decreased cerebrovascular reactivity [CVR] indicating reduced ability of the cerebral vasculature to adjust CBF).] Cerebral blood flow (CBF) is tightly coupled with metabolism underlying cognition by increasing local delivery of oxygen and glucose to support neural function, and as such is an indirect measure of neural activity and vascular function. [Animal models suggest reduced CBF (aka, hypoperfusion) contributes to AD-like neurodegeneration by increasing amyloid-? accumulation and tau phosphorylation--the hallmark neuropathology of AD. Translating these findings to humans is critical to identify and refine biomarkers of AD and ultimately improve early detection and treatment.] We have shown altered CBF in prefrontal and medial temporal lobe regions in older adults at genetic (APOE ?4 carriers) or cognitive (mild cognitive impairment; MCI) risk for AD that is associated with memory and executive function, implicating CBF as a potential biomarker of AD. This application aims to elucidate the link between the vascular and neurodegenerative pathophysiological process of AD and the emergence of clinical symptoms to lead to an improved mechanistic understanding of cognitive decline. Thus, the current application: [1) examines the association between neurovascular (CBF) and cerebrovascular (CVR) function and cognition in at-risk older Veterans and tests potential AD-related mechanisms (e.g., cerebral spinal fluid [CSF] AD biomarkers) that mediate this relationship, 2) examines whether cerebrovascular function moderates the relationship between CBF and CSF biomarkers, and 3) examines moderating effects of individual risk factors (e.g., increased arterial stiffness, elevated sedentary time, APOE ?4).] This study will examine cognitive, vascular, and brain function in 120 English-speaking non-demented Veterans aged 65+ with at least 2 CVD risk factors, placing them at increased risk for cognitive decline. Assessments include well-validated and standardized cognitive testing (e.g., NIH Toolbox), state-of-the-art MR imaging (to measure CBF and CVR), comprehensive vascular function assessment (including carotid-femoral pulse wave velocity, blood pressure, carotid ultrasound), lumbar puncture to assay CSF AD biomarkers (including A?42, p-tau181, and total tau), accelerometry to assess physical activity/sedentary level, and APOE genotyping. [This novel proposal aims to test the central hypothesis that CBF and/or CVR support cognitive performance and this relationship is mediated by the presence of CSF biomarkers of AD neurodegeneration, suggesting a synergistic contribution of neurovascular and cerebrovascular dysfunction to neurodegeneration and cognitive decline in older at-risk Veterans.] The completion of the proposed aims will achieve the following goals that could guide future research in early dementia detection and prevention: 1) refine the prevailing biomarker model of AD by more firmly establishing the independent or combined contribution of neuropathological and cerebrovascular AD risk factors in the cascade of events precipitating AD, 2) establish prognostic utility of imaging, neuropsychological, neuropathological, and vascular biomarkers to detect cognitive decline, and 3) improve mechanistic understanding of AD risk and identify potential therapeutic targets that will ultimately inform interventions to prevent or delay the onset of AD.